Diabetes is divided into two types—i.e., insulin-dependent type 1 diabetes and insulin-independent (insulin-resistant) type 2 diabetes which is found in 90% or more of diabetic patients.
In insulin-resistant type 2 diabetic patients, internal insulin does not take effect completely so blood glucose must be controlled in another way, and an oral hypo-glycemic agent is typically used.
Currently, most antidiabetics control blood glucose by a mechanism of action that affects one target organ such as the liver, pancreas or muscle. For example, sul-fonlyureas act directly on the pancreas to cause insulin secretion, and metformins have the mechanism of action of preventing glucolysis in the liver. However, a single drug hardly accomplishes the expected effect in many cases and each drug also has its side effects. For example, sulfonylureas have problems of decreasing the function of the pancreas and incurring hypoglycemia due to excessive secretion of insulin, and metformins cause gastroenteric disorders or renal toxicity. Glitazones also have side effects of weight gain, serious heart failure, etc. Meanwhile, incretin-related drugs such as DPPIV inhibitors or Exenatide, which have recently entered the market, are noted as medicines for solving problems such as increase of glucagon production, gradual decrease of the β-cell function in the pancreas, incurrence of hypoglycemia, weight gain, etc. which cannot be solved by traditional antidiabetics. However, DPPIV inhibitors have a marginal effect, and it is especially reported that Galvus has the side effect of skin toxicity. Furthermore, Exenatide has a disadvantage in that it must be given by means of injection.
As described above, most conventional antidiabetics have various problems and side effects, and it is highly necessary to develop innovative antidiabetics which can be used for the treatment of diabetes effectively and safely.
GPR120 agonists, which are noted for possible treatment of type 2 diabetes, are known to have (1) an antidiabetic effect caused by the actions of increasing incretin hormone in intestinal cells, (2) anti-inflammatory action in macrophages, and (3) an action of improvement on insulin resistance in lipocytes. They are also known as a possible treatment of type 1 diabetes by the action of improvement on proliferation of pancreas cells.
G protein-coupled receptor 120 (GPR120) is expressed copiously in intestines, lungs, adipose tissue, and macrophages which induce inflammation, and is activated by long chain free fatty acid (FFA). GPR120 stimulates the secretion of glucagon-like peptide-1 (GLP-1) by FFA. GLP-1, an incretin hormone, is known to stimulate the secretion of insulin in the pancreas dependently on blood glucose level, and also to have the effect of improvement of insulin resistance, proliferation of β-cells, appetite loss and increase of satiety. Recently, GPR120 is known to relate with improvement of insulin resistance and anti-inflammatory effect, and therefore, it is regarded as a target for developing a drug to effectively improve insulin resistance, type 2 diabetes and obesity involving low-level chronic inflammation. Furthermore, in animal experiments of type 1 diabetes, GPR120 agonists are reported to improve the secretion of insulin by the action of proliferation of β-cells.
Considering the above, researches on GPR120 agonists are actively in progress. In the representative compounds presented as GPR120 agonists, two aryl groups are connected with a center bridge structure, and the characteristic feature is that one of two aryl groups is substituted by carboxylic acid. GPR120 agonist compounds are disclosed in WO2011/159297, WO2010/080537, WO2010/104195, WO2010/048207, WO2009/147990, WO2008/066131, WO2008/103500 and WO2008/139879.